Photosensitizing Antihypertensive Drug Use and Risk of Cutaneous Squamous Cell Carcinoma

K.A. Su; L.A. Habel; N.S. Achacoso; G.D. Friedman; M.M. Asgari

Disclosures

The British Journal of Dermatology. 2018;179(5):1088-1094. 

In This Article

Discussion

In this large cohort study conducted in a community–based comprehensive integrated healthcare delivery system, we found a 17% increase in risk of cSCC in NHW patients with hypertension who received photosensitizing ADs during follow–up compared with nonusers of ADs. Each class of photosensitizing AD showed small increases in risk, but combination thiazide diuretics were the only class to attain statistical significance. In addition, there was a modest increase in risk with increasing number of prescriptions of photosensitizing ADs. Risk of cSCC was increased among users of photosensitizing ADs regardless of history of actinic lesions. Use of ADs with unknown photosensitizing potential was associated with a statistically significant 11% increase in risk and nonphotosensitizing ADs were not associated with increased risk of cSCC. Findings among new users of these drugs were generally consistent with those of all users, but statistical significance was not evident owing to the small number of new users.

Results of previous studies of ADs and the risk of skin cancer have been inconsistent.[17–24] While some have shown increased risk with the use of potassium–sparing and combination diuretics,[19,24] but not loop or thiazide diuretics,[19,20,24] several studies, including one at KPNC, have shown a significant association between thiazide diuretic use and increased SCC risk.[14,15,18,22] ACE inhibitors and ARBs have been associated with a reduced risk of keratinocyte cancers in some studies[17,21] and an increased risk in others.[22,24] Beta blockers, which are not widely recognized as photosensitizing,[1–5] have been associated with an increased risk of lip cancer and SCC in some studies.[14,20] To our knowledge, the present study is the first to examine cSCC risk associated with the use of alpha blockers and central agonists. A recent meta–analysis of observational studies examining the use of ADs and risk of keratinocyte carcinoma found that diuretics are associated with increased SCC risk, while ACE inhibitors and ARBs are associated with decreased SCC risk in high–risk individuals, and CCBs and beta blockers are not associated with SCC risk.[27]

The chemical structures of photosensitizing drugs permit the absorption of UVR,[8–10] the primary risk factor for SCC.[28] They promote sunburn and may be carcinogenic, triggering phototoxic or photoallergic reactions.[8] These effects, in turn, may induce DNA damage and chronic inflammation. Observed differences is cSCC risk among various photosensitizing drugs may be due to differences in their biological effects and differences in study design.

Strengths of this study include its setting in a comprehensive healthcare system with unified electronic patient records that allowed ascertainment of physicians' diagnosis of hypertension, pathological verification of the diagnosis of cSCC, and documentation of dispensing of the pharmaceutical drugs studied, thus eliminating the possibility of recall bias in patients. We were also able to document and attempt to account for healthcare utilization as possibly influencing our findings.

However, the main associations that we observed, although statistically significant, were quite small in magnitude and could have been affected by the study's limitations. Although we adjusted for several baseline characteristics, residual confounding could have affected our findings. We were unable to adjust for sun exposure but could ascertain and control for prior AKs, which may be viewed as risk factors for cSCC that were related to sun exposure. Although drug–related acute adverse reactions to sunlight could influence the choice of ADs or lead to a change of AD, it seems unlikely that this would have a major effect on our findings or that differences in sun exposure would be related to which ADs are prescribed. While our use of prescriptions filled at KPNC pharmacies as a surrogate for medication use could have led to exposure misclassification, it is unlikely that those with pharmacy benefits would have filled their prescriptions elsewhere. There was considerable overlap between the treatment groups, and concurrent use of ADs from multiple different classes after cohort entry may have influenced the cSCC risk observed in each treatment group.

In conclusion, we observed a modest association between increasing exposure to photosensitizing ADs and increasing risk of cSCC. Additional studies, including those that control for potential confounding factors, such as sun exposure, are needed to confirm our findings and further evaluate the risks associated with specific drug classes. In the meantime, patients taking photosensitizing ADs may benefit from education on safe sun practices and closer screening for cSCC given the potential public health implications associated with widespread use of these common medications.

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